The generality of a decreased cognitive function in man with senescence is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness in higher mammals, including humans.
Factors such as decreased acetylcholine synthesis and impairment of cholinoreceptive neurons in aged animals have been related to decreased cognitive function. Similarly, choline supplementation of 10 month old mice improves performance on passive avoidance tasks. Even so, the molecular basis of the decreased cognitive function is higher animals is unknown. P. Davies, and A. Verth, Brain Res. 138: 395 (1978); T. D. Reisine, H. I. Yamamura, E. D. Bird, E. Spokes and S. J. Enna, Brain Res. 159: 447 (1978); P. I. White, M. J. Goodhardt, J. P. Kent, C. R. Hiley, L. H. Carrasco, I. E. Williams, and D. M. Bowen, Lancet i: 668 (1977); E. McGeer and P. L. McGeer, IN: Aging Vol. 3; Neurobiology of Aging (R. D. Terry and S. Gershon, Eds. p. 384 (1977); E. K. Perry, R. H. Perry, P. Gibson, G. Blessed and B. E. Tomlinson, Neurosci. Lett. 6: 85 (1977); N. Sims, D. M. Bowen and A. N. Davison, Biochem. J., 196: 867 (1981); A. S. Lippa, R. W. Pelham, B. Beer, D. J. Critchett, R. L. Dean, and R. T. Bartus, Neurobiology of Aging 1: 13 (1980); R. T. Bartus, R. L. Dean, J. A. Goas and A. S. Lippa, Science 209: 301 (1981).
Related work by the present inventors has shown that during hypoxia, pharmacological agents that enhance calcium influx into nerve terminals (e.g., 4-aminopyridine and 3,4-diaminopyridine) partially restore cholinergic activity and behavior by stimulation of the calcium dependent release of acetylcholine. G. E. Gibson and C. Peterson, Fed. Proc. 65: 200 (1981); G. E. Gibson and C. Peterson, Biochem. Pharm. 32: 111 (1982); C. Peterson, C. J. Pelmas and G. E. Gibson, Neurosci. Abstr. 7, 494 (1981). Cholinergic deficits occur during mild acute hypoxia. Low oxygen tensions impair memory in man, produce behavioral deficits in animals and reduce the synthesis and the calcium dependent release of acetylcholine in animals.
Further, pharmacological interruption of the cholinergic system produces decreases in cognition similar to those during senescence and mild acute hypoxia. D. A. Drachman, Neurology 27: 783 (1977); D. A. Drachman, D. Noffsinger, B. J. Sahakian, S. Krudziel and P. Fleming, Neurobiology of Aging 1: 39 (1981).
Prior to this invention and their related work on hypoxia, the present inventors were not aware of the use of any diaminopyridines in the treatment of any disease or condition in man or lower animals. 4-aminopyridine has been used to treat disorders of neuromuscular transmission, e.g., botulinum toxin poisoning and myasthenia gravis. H. Lundh, O. Nilsson and I. J. Rosen, Neurol. Neurosurg. Psychiat. 40: 1109 (1977); S. Agoston, P. Van Weerden and A. Broekert, Anaesth. 50: 383 (1978); H. Lundh, O. Nilsson and I. J. Rosen, Neurol. Neurosurg. Psychiat. 42: 171.